Ping Xingjie, Meyer Michelle J, Zahn Nicolas M, Golani Lalit K, Sharmin Dishary, Pandey Kamal P, Revanian Sepideh, Mondal Prithu, Jin Xiaoming, Arnold Leggy A, Cerne Rok, Cook James M, Divović Branka, Savić Miroslav M, Lippa Arnold, Smith Jodi L, Witkin Jeffrey M
Department of Anatomy and Cell Biology, Indiana University/Purdue University, Indianapolis, Indiana, USA.
Department of Chemistry & Biochemistry, Milwaukee Institute of Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, USA.
Drug Dev Res. 2023 May;84(3):527-531. doi: 10.1002/ddr.22042. Epub 2023 Feb 7.
A series of imidazodiazepines has been developed that possess reduced sedative liabilities but retain efficacy in anticonvulsant screening models. The latest of these compounds, (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole known as KRM-II-81) is currently awaiting advancement into the clinic. A deuterated structural analog (D5-KRM-II-81) was made as a potential backup compound and studied here in comparison to KRM-II-81. In the present study, both compounds significantly prevented seizures in mice induced by 6 Hz (44 mA) electrical stimulation without significantly altering motoric function on a rotarod after intraperitoneal administration. Both compounds also significantly prevented clonic seizures, tonic seizures, and lethality induced by pentylenetetrazol in mice when given orally. D5-KRM-II-81 had a slightly longer duration of action against clonic and tonic seizures than KRM-II-81. Oral administration of 100 mg/kg of either KRM-II-81 or D5-KRM-II-81 was significantly less disruptive of sensorimotor function in mice than diazepam (5 mg/kg, p.o.). The present report documents that D5-KRM-II-81 represents another in this series of imidazodiazepines with anticonvulsant activity at doses that do not impair sensorimotor function.
已开发出一系列咪唑二氮䓬类化合物，它们具有降低的镇静作用，但在抗惊厥筛选模型中仍保持疗效。这些化合物中的最新一种，即(5-(8-乙炔基-6-(吡啶-2-基)-4H-苯并[f]咪唑并[1,5-α][1,4]二氮䓬-3-基)恶唑，称为KRM-II-81，目前正等待进入临床试验。制备了一种氘代结构类似物(D5-KRM-II-81)作为潜在的备用化合物，并在此与KRM-II-81进行比较研究。在本研究中，两种化合物在腹腔注射后均能显著预防6Hz(44mA)电刺激诱导的小鼠癫痫发作，且对转棒试验中的运动功能无显著影响。口服给药时，两种化合物还能显著预防戊四氮诱导的小鼠阵挛性癫痫发作、强直性癫痫发作和致死性。D5-KRM-II-81对阵挛性和强直性癫痫发作的作用持续时间比KRM-II-81略长。口服100mg/kg的KRM-II-81或D5-KRM-II-81对小鼠感觉运动功能的干扰明显小于地西泮(5mg/kg，口服)。本报告证明，D5-KRM-II-81是该系列咪唑二氮䓬类化合物中的另一种，在不损害感觉运动功能的剂量下具有抗惊厥活性。
